WO1991007366A1 - Procede de preparation de r(+)-terodiline et de ses sels - Google Patents

Procede de preparation de r(+)-terodiline et de ses sels Download PDF

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Publication number
WO1991007366A1
WO1991007366A1 PCT/SE1990/000740 SE9000740W WO9107366A1 WO 1991007366 A1 WO1991007366 A1 WO 1991007366A1 SE 9000740 W SE9000740 W SE 9000740W WO 9107366 A1 WO9107366 A1 WO 9107366A1
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WO
WIPO (PCT)
Prior art keywords
terodiline
process according
hydrochloride
enantiomer
tartaric acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/SE1990/000740
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English (en)
Inventor
Nils Åke JÖNSSON
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Health AB
Original Assignee
Kabi Pharmacia AB
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Filing date
Publication date
Application filed by Kabi Pharmacia AB filed Critical Kabi Pharmacia AB
Publication of WO1991007366A1 publication Critical patent/WO1991007366A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/86—Separation
    • C07C209/88—Separation of optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains

Definitions

  • the present invention relates to optical resolution of racemic mixtures into the individual enantiomers. More speci- fically, the invention relates to a novel process for prepa ⁇ ring optically pure R(+)-terodiline and salts thereof from a racemic mixture of terodiline [(+/-)-N-tert.-butyl-1-methyl- 3,3-diphenylpropylamine] .
  • Terodiline is an antichlorinergic substance which in the form of its hydrochloride (terodiline hydrochloride) is widely used to treat urinary incontinence. It is known that the anticholinergic activity mainly resides in the R(+)-form of the compound, and that the R(+)- and S(-)-forms are diffe- rently metabolized (B. Lindeke, ⁇ . Ericsson, A. J ⁇ nsson and B. Vangbo. Xenobiotica 12 (1987) 1269). It is thus desirable to use the pure R(+) enantiomer in therapy.
  • the primary object of the invention is to provide a novel process for recovering optically pure R(+)-terodiline and pharmaceutically acceptable salts thereof from racemic terodiline.
  • a special object of the invention is to provide a pro ⁇ cess of the indicated type, which does not require expensive reactants, is simple and convenient to carry out and produces an end product of high optical purity in high yields.
  • the R(+)-terodiline hydrocloride obtained in step c) is preferably d) subjected to one or more re-crystallizations from water. If desired, the R(+)-terodiline hydrochloride obtained from step c) or d) may e) be converted into the free base or into a different pharmaceutically acceptable salt by means of convention ⁇ al procedures.
  • step a) it is preferred to use from about 0.8 to about 1.5 moles of (+)-tartaric acid per 1 mole of the tero ⁇ diline racemate, most preferably approximately equimolar amounts.
  • Other preferred embodiments of the claimed process are disclosed below and/or are indicated in the sub-claims.
  • most of the S(-)-terodi- line is first removed from a solution of the racemate in a suitable solvent, preferably ethanol, by precipitation with an approximately equimolar amount of L(+)-tartaric acid, whereupon amine enriched in the (+)-form is recovered from the mother liquor and the (+)-hydrochloride is precipitated from water with hydrochloric acid.
  • a suitable solvent preferably ethanol
  • An alternative preferred embodiment comprises the same initial step as the first embodiment, viz. precipitation of S(-)-terodiline hydrogen L(+)-tartrate.
  • the mother liquor from this precipitation step is then concentrated to a thick syrup and worked up without isolation of the free amine.
  • the syrup is dissolved in water whereupon the solution is ad ⁇ justed to pH about 5 to 6 using a water soluble base, pre ⁇ ferably ammonia, that forms readily water soluble salts with L(+)-tartaric acid.
  • R(+)-terodiline hydrochloride is then precipitated from the solution by the addition of a readily water soluble chloride salt that forms a readily water soluble salt with L(+)-tartaric acid, the preferred salt being ammonium chloride.
  • the crude (+)-terodiline hydrochloride thus obtained is preferably further purified by recrystallization from water.
  • One or two such crystallizations produce R(+)-terodiline hydrochloride of better than 99% enantiomeric purity and a melting point of 224-225°C.
  • the racemic material occurs in several polymorphic forms, the highest melting of which melts at 186-188°C) .
  • the obtained hydrochloride can be converted into the free amine or to other pharmaceutically acceptable salts in conventional manner.
  • (+/-)-Terodiline (2.50 kg; 8.88 ol) and L(+)-tartaric acid (1.34 kg; 8.93 mol) are dissolved in 10 L of 95% ethanol at 40-50°C.
  • the clear solution is chilled to about 35°C and seeded with about 1 g of pre-prepared S(-)-terodiline hydro ⁇ gen L(+)-tartrate.
  • the crystalline material is sucked off and washed with about 3 L of ethanol and dried to yield 1.95 kg of S(-)-terodiline hydrogen L(+)-tartrate.
  • the combined mother liquors and washings from the above procedures are evaporated under reduced pressure at 50-100°C to a thick syrup. This is dissolved in about 10 L of hot water and the solution is made strongly alkaline with 45% aqueous sodium hydroxide solution. The free amine separates as an upper layer which is collected and washed once with water. It is suspended in about 8 L of water at about 50°C and neutralized to about pH 4-5 with concentrated hydrochlo ⁇ ric acid (about 380 ml). The solution is then chilled to about 10°C for several hours. The precipated salt is sucked off and washed with cold water. A dried sample melts at 215- 220°C. The product is recrystallized from 4 L of boiling water with cooling and isolation as above.
  • S(-)-Terodiline hydrogen L(+)-tartrate is isolated from 844 g (3.00 mol) of (+/-)-terodiline using 450 g (3.00 mol) of L(+)-tartaric acid in 4.5 L of 95% ethanol following the procedure of Example 1.
  • the combined mother liquors and washings are concentrated to a thick syrup at 50-100°C under vacuum.
  • the syrup is dissolved in 6 L of boiling water. Remaining alcohol is removed by distilling off about 1 L of solvent.
  • the volume is restored by the addition of water and ammonia is added to pH 5-6. Solid ammonium chloride (120 g) is then added and the solution is allowed to cool to room temperature.
  • the precipitated crude R(+)-terodiline hydrochloride is sucked off and washed with cold water.
  • the moist material (a dried sample melts at about 218-220°C) is recrystallized from 4 and 2 L of water to yield 310 g (65% of theoretical) of pure R(+)-terodiline hydrochloride melting at 224-225°C (Kofler bench) and having an enantiomeric purity, determined as in Example 1, of better than 99%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Audible-Bandwidth Dynamoelectric Transducers Other Than Pickups (AREA)

Abstract

Nouveau procédé de préparation du R(+)-énantiomère de térodiline (N-tert.butyle-1-methyle-3,3-diphénylpropylamine) et de ses sels pharmaceutiquement acceptables, par résolution optique d'un mélange racémique de térodiline à l'aide d'acide tartarique, comprenant les étapes consistant (a) à éliminer la majeure partie de l'énantiomère de S(-)-térodiline du mélange racémique de térodiline par précipitation à l'aide d'acide L(+)-tartarique dans un solvent organique, (b) à récupérer de la solution mère de l'étape (a) un produit de térodiline enrichi dans le (+)-énantiomère, (c) à former l'hydrochlorure dudit produit de térodiline dans une solution aqueuse de manière à précipiter l'hydrochlorure R(+)-térodiline à partir de ladite solution aqueuse. L'hydrochlorure R(+)-térodiline obtenu dans l'étape (c) est de préférence (d) soumis à une ou à plusieurs recristallisations à partir d'eau. L'hydrochlorure de R(+)-térodiline obtenu dans les étapes (c) ou (d) peut, si désiré, (e) être transformé en la base libre ou un sel pharmaceutiquement acceptable différent, au moyen de techniques classiques.
PCT/SE1990/000740 1989-11-16 1990-11-15 Procede de preparation de r(+)-terodiline et de ses sels Ceased WO1991007366A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP89850401A EP0427904A1 (fr) 1989-11-16 1989-11-16 Procédé de préparation de R(+)-terodiline et de ses sels
EP89850401.4 1989-11-16

Publications (1)

Publication Number Publication Date
WO1991007366A1 true WO1991007366A1 (fr) 1991-05-30

Family

ID=8203272

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1990/000740 Ceased WO1991007366A1 (fr) 1989-11-16 1990-11-15 Procede de preparation de r(+)-terodiline et de ses sels

Country Status (4)

Country Link
EP (1) EP0427904A1 (fr)
JP (1) JPH05502027A (fr)
AU (1) AU6746290A (fr)
WO (1) WO1991007366A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05155820A (ja) * 1991-12-06 1993-06-22 Kissei Pharmaceut Co Ltd Ｎ−ｔｅｒｔ−ブチル−１−メチル−３，３−ジフェニルプロピルアミン塩酸塩の結晶多形およびその製造方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5492933A (en) * 1993-10-08 1996-02-20 Sepracor, Inc. Methods and compositions for treating urinary incontinence and other disorders using optically pure R-terodiline and hydroxylated derivatives thereof
US6229190B1 (en) 1998-12-18 2001-05-08 Maxim Integrated Products, Inc. Compensated semiconductor pressure sensor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2166732A (en) * 1984-10-09 1986-05-14 Nisshin Flour Milling Co Process for preparing l-carnitine and salts thereof
EP0287523A2 (fr) * 1987-03-18 1988-10-19 SIGMA-TAU Industrie Farmaceutiche Riunite S.p.A. Procédé de préparation de (-) N-acétylaminocarnitine et de (+) N-acétylaminocarnitine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2166732A (en) * 1984-10-09 1986-05-14 Nisshin Flour Milling Co Process for preparing l-carnitine and salts thereof
EP0287523A2 (fr) * 1987-03-18 1988-10-19 SIGMA-TAU Industrie Farmaceutiche Riunite S.p.A. Procédé de préparation de (-) N-acétylaminocarnitine et de (+) N-acétylaminocarnitine

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN, Vol. 6, No. 11, (C-88); JP,A,56 135 446, Published 22 October 1981. *
PATENT ABSTRACTS OF JAPAN, Vol. 6, No. 11, (C-88); JP,A,56 135 447, Published 22 October 1981. *
XENOBIOTICA, Vol. 17, No. 11, 1987, B. LINDEKE et al., "Biotransformation of Terodiline. III. Opposed Stereoselectivity in the Benzylic and Aromatic Hydroxylations in Rat Liver Microsomes", pages 1269-1278. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05155820A (ja) * 1991-12-06 1993-06-22 Kissei Pharmaceut Co Ltd Ｎ−ｔｅｒｔ−ブチル−１−メチル−３，３−ジフェニルプロピルアミン塩酸塩の結晶多形およびその製造方法

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Publication number Publication date
JPH05502027A (ja) 1993-04-15
AU6746290A (en) 1991-06-13
EP0427904A1 (fr) 1991-05-22

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